Infection in both human and veterinary medicine is often caused by infection with bacteria of the Staphylococcus genus. Staphylococci are commensals of healthy mammals and birds and may be found on the skin and in associated glands, the nares, and transiently in the gastrointestinal tract as well as on the mucous membranes of the upper respiratory and lower urogenital tracts. While many strains and species of Staphylococcus do not cause disease, certain strains and species are capable of opportunistic pathogenicity. Two major pathogenic species of Staphylococcus of medical and veterinary significance are Staphylococcus aureus and Staphylococcus pseudintermedius. Staphylococcus aureus is associated with skin and post-operative wound infections, while Staphylococcus pseudintermedius is commonly associated with pyogenic skin and post-operative wound infections in dogs and cats. Staphylococcus pseudintermedius has been identified as the main pathogenic species of veterinary significance in the Staphylococcus pseudintermedius group (SIG), which includes the strains Staphylococcus intermedius, Staphylococcus pseudintermedius, and Staphylococcus delphini. 
Treatment of Bacteria with Antibiotics
The treatment of Staphylococcus bacteria can be difficult, particularly when subjects are infected with antibiotic-resistant strains. Bacterial infection by Staphylococcus is usually treated by the administration of β-lactam antimicrobials, a class of antimicrobials that target penicillin binding proteins (PBPs) which function in bacterial cell wall biosynthesis. These antimicrobials have bactericidal activity and function by inhibiting biosynthesis of the bacterial cell wall, resulting in high internal osmotic pressure, causing the bacteria to lyse. However, the use, overuse and misuse of antimicrobials in the treatment of bacterial infections has resulted in the emergence of antimicrobial resistant bacteria, to which the Staphylococcus genus is particularly prone. Resistance mechanisms in some species of Staphylococcus bacteria include the secretion of β-lactamase enzymes capable of hydrolysing the β-lactam ring of β-lactam antimicrobials. To address this form of resistance, β-lactamase inhibitors, such as clavulanic acid are typically co-administered together with β-lactam antimicrobials, or synthetic analogues of penicillin, such as methicillin, that are not substrates of β-lactamase, can be used.
Recently, even combination treatment has proved ineffective against antibiotic resistant strains of Staphylococcus. The emergence of methicillin-resistant Staphylococcus aureus isolates (MRSA) has effectively prevented the use of methicillin and other β-lactam antimicrobials that are not inactivated by β-lactamases. MRSA isolates have now been found to possess the mecA resistance gene which encodes mutated penicillin binding proteins or PBPs and confers resistance to penicillin, as well as to its analogues, and other β-lactam antimicrobials, including most cephalosporins and carbapenems. The issue of MRSA is often encountered in hospitals where MRSA bacterial isolates have been transferred to patients, as hospital-acquired MRSA (HA-MRSA) which is often maintained within hospitals through the colonisation of hospital equipment and staff. Unfortunately, patients who are immunosuppressed, have wounds or other trauma, are predisposed to easily contract MRSA infections, as well as infections with other species of staphylococci. This has caused many hospitals to implement anti-MRSA measures so as to reduce the incidence of HA-MRSA infections. A more recent concern has been the emergence of MRSA strains outside of hospitals, referred to as community-acquired MRSA (CA-MRSA). These strains are often even more virulent than HA-MRSA strains and may cause necrotising fasciitis.
In addition to MRSA, methicillin-resistance has also been observed in other species of staphylococci. For example, many strains of non-pathogenic, coagulase-negative species of Staphylococcus (MR-CNS) and Staphylococcus pseudintermedius (MRSP) are known to be methicillin-resistant. Other resistant species include the Gram negative MDR Pseudomonas aeruginosa, and MDR Escherichia coli and Enterobacter species and the Gram positive vancomycin resistant Enterococcci (VRE) and resistant Streptococcus spp.
The emergence of resistance to antibiotics has increased the need to provide alternative compounds capable of inhibiting multi-resistant bacterial strains, such as MRSA and MRSP.
Polyether Ionophores
Carboxyl polyethers, also known as polyether antibiotics or polyether ionophores, form electrically neutral complexes with monovalent or divalent cations, catalysing electrically silent exchanges of cations or protons across a variety of biological membranes. These compounds have been reported as showing a high degree of promise for the potential control of drug-resistant bacterial and protozoal infections however their use is severely limited by their high toxicity. These molecules function by rendering cell or intracellular membranes permeable to cations which are normally asymmetrically distributed across biological membranes thereby forming steep concentration gradients. Examples of polyether ionophores include lasalocid, monensin, narasin, salinomycin, semduramicin, maduramicin and laidlomycin.
However, the acute toxicity of these compounds due to their erythrocyte lysing activity and cardiac toxicity has effectively prevented their use in vivo. The main obstacle to the use of polyether ionophores as drugs to control human diseases is the issue of toxicity. In one example, as reported by Naujokat and Steinhart (2012, J Biomed Biotechnol 950658), considerable toxicity of salinomycin was reported in humans. In this case, the accidental inhalation and swallowing of about 1 mg/kg salinomycin by a 35-year-old male human, resulted in severe acute and chronic salinomycin toxicity with acute nausea together with photophobia, leg weakness, tachycardia and blood pressure elevation and a chronic (day 2 to day 35) creatine kinase elevation, myoglobinuria, limb weakness, muscle pain, and mild rhabdomyolysis. The European Food Safety Authority has recently published risk assessment data declaring an acceptable daily intake (ADI) of 5 μg/kg salinomycin for humans, since daily intake of more than 500 μg/kg salinomycin by dogs leads to neurotoxic effects, such as myelin loss and axonal degeneration (Naujokat and Steinhart, 2012, supra). In another example, Liu (1982, Polyether Antibiotics. Naturally Occurring Acid Ionophores. Volume 1. Biology. J. W. Westley. New York, Marcel Dekker Inc: 43-102) cites the high oral and parenteral toxicity of polyether ionophores is the likely reason why there has been no report on the in vivo antimicrobial activity of polyether ionophores.
The only current applications for polyether ionophores of which the applicant is aware, is their application as orally administered agents in veterinary medicine as controls of coccidiosis and for growth promotion.
Furthermore, not all polyether ionophores have shown significant activity against gram-positive bacteria such as Staphylococcus aureus and most do not have broad-spectrum activity against gram-negative bacteria. In view of the considerable toxicity in mammals, as reported by Naujokat and Steinhart (2012 supra), salinomycin has only been used as a coccidistat and growth promoter in livestock, and is not regarded as a suitable candidate for human drug development.
There remains a need for alternative antimicrobials in the treatment of infection by multi-resistant bacteria, such as MRSA and MRSP. However, as reported by the Infectious Diseases Society of America and the European Centre for Disease Control and Prevention, few new drugs are being developed that offer promising results over existing treatments, and even fewer of these are specifically administered for the treatment of staphylococci (Gilbert et al. 2010, Clinical Infectious Diseases, 50(8):1081-1083).
The object of the present invention is to overcome some or all of the shortcomings of the prior art.
The discussion of the background art set out above is intended to facilitate an understanding of the present invention only. The discussion is not an acknowledgement or admission that any of the material referred to is or was part of the common general knowledge as at the priority date of the application.